The present invention provides a cyclic hexapeptide or a salt thereof, a method of its production, and an endothelin receptor antagonist containing said cyclic hexapeptide or a pharmacologically acceptable salt thereof.
Endothelin (ET), a vasoconstrictive peptide comprising 21 amino acids, is isolated from the culture supernatant of the endothelial cells of porcine aortas and structurally determined by Yanagisawa et al. in 1988 Yanagisawa et al., Nature, Vol. 332, pp. 411-412!. Research into endothelin-encoding genes has demonstrated that endothelin occurs in 3 structurally similar peptides, designated endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), respectively.
On the other hand, two types of endothelin receptors are known: endothelin A receptors, which show higher affinity for ET-1 and ET-2 than for ET-3, and endothelin B receptors, which show equivalent affinity for ET-1, ET-2 and ET-3. In the part, endothelin A receptors were thought to be present in vascular smooth muscle and to induce smooth muscle contractions, endothelin B receptors to be present in vascular endothelial cells and to induce smooth muscle relaxation. In recent years, however, endothelin B receptors have been shown to be involved in vascular smooth muscle contractions as well Biochemical and Biophysical Research Communications, Vol. 175(2), 556-561 (1991); Journal of Cardiovascular Pharmacology, Vol. 20 (Suppl. 12), S11-S14 (1992)!. There is therefore a need for the development of endothelin B receptor antagonists, as well as endothelin A receptor antagonists.
Since the development of endothelin, there have been intensive investigations in search of compounds that antagonize endothelin receptors, with the aim of developing therapeutic agents for diseases caused by endothelin. For example, cyclic peptides showing endothelin receptor antagonistic action are disclosed in EP0436189A1 and EP0528312A2. The cyclic peptide of Japanese Patent Unexamined Publication No. 261198/1992, in particular, is known to be very low in affinity for endothelin B receptors, though it has affinity for endothelin A receptors. The compound disclosed in Japanese Patent Unexamined Publication No. 261198/1992 is therefore faulty in that vascular smooth muscle contractions mediated by endothelin B receptors are not suppressed satisfactorily, though it suppresses vascular smooth muscle contractions mediated by endothelin A receptors.. On the other hand, the compound disclosed in EP0528312A2 is known to be an excellent endothelin receptor antagonist in that it has affinity not only for endothelin A receptors but also for endothelin B receptors. However, there is a need for development of an endothelin B receptor antagonist that shows better affinity for endothelin B receptors, so as to efficiently suppress vascular smooth muscle contractions mediated by such receptors.
The object of the present invention is to provide a compound having the antagonistic activity on endothelin B receptors with greater potency than for other types of endothelin receptors.